Globally, HIV continues to present a significant public health challenge. As of 2022, approximately 39 million individuals are living with HIV, with women and girls accounting for 53% of this population. Each year, around 1.2 million pregnancies occur among women with HIV, leading to approximately 130,000 new pediatric HIV infections and a total of 1.5 million children living with HIV. Without medical intervention, the risk of mother-to-child transmission (MTCT) of HIV is substantial. During pregnancy, the transmission risk ranges from 5-10%, increases to 15-20% during labor and delivery, and further escalates to 15-25% through breastfeeding. The monthly transmission risk through breastfeeding is approximately 1%. However, the implementation of effective ART during pregnancy can significantly reduce this risk, lowering it to less than 1%.

Prevention of MTCT of HIV involves a multi-faceted approach. Early HIV screening for pregnant women is crucial for timely intervention. Women who test positive for HIV should initiate ART if not already on therapy. In cases where viral loads remain high, cesarean sections may be recommended to minimize transmission risk during delivery. Additionally, pre-exposure prophylaxis (PrEP) is provided to women at high risk of acquiring HIV during pregnancy and breastfeeding. Formula feeding is an alternative that entirely eliminates the risk of HIV transmission through breast milk.

Despite the effectiveness of ART in reducing HIV transmission, certain factors can still lead to transmission. These include unawareness of HIV status, lack of access to ART, new HIV infections during pregnancy, inconsistent adherence to ART regimens, and subclinical mastitis, which can increase viral load in breast milk. Additionally, discrepancies in viral loads between plasma and breast milk and compromised integrity of the infant's gut mucosa can heighten susceptibility to infection.

In low and middle-income settings, breastfeeding has been the primary choice since 1996 due to its significant benefits in reducing mortality and morbidity among children compared to formula feeding. This approach became the standard of care in these settings. Conversely, in high-income settings where formula feeding is more accessible, breastfeeding was discouraged due to concerns about potential transmission of HIV. As a result, most studies on breastfeeding and HIV have been conducted in low and middle-income settings, often using outdated treatment regimens. 

Several key studies shed light on the transmission rates and efficacy of different antiretroviral regimens in preventing mother-to-child transmission of HIV during breastfeeding. 

The BAN study, conducted in 2010, focused on mothers receiving nevirapine intrapartum and infants receiving nevirapine within 72 hours of birth, along with zidovudine until seven days postpartum. The study randomized participants into different treatment arms, including a control group. Results showed a 6% transmission rate in the control group, while rates were 1.7% for infant regimen and 2.9% for maternal regimen. Notably, even among non-transmitting mothers, 15% had detectable viral loads in breast milk, suggesting that breast milk viral load doesn't always lead to transmission. The study concluded that maternal plasma viral load under 40 copies/ml had less than 1% detectable viral load in breast milk, with no transmission in women with plasma viral load under 100 copies/ml.

The PROMISE study, which randomized participants to maternal antiretroviral therapy (ART) or infant prophylaxis, showed no significant difference in HIV transmission rates up to 18 months. Both strategies resulted in transmission rates of less than 1%, although the study used older regimens like lopinavir twice daily, which are no longer common.

Two recent studies, VESTED and DOLPHIN2, have investigated the efficacy of dolutegravir in preventing mother-to-child transmission of HIV. The VESTED study enrolled women in the second trimester of pregnancy and randomized them to receive either a dolutegravir regimen or an efavirenz regimen. Each arm consisted of 200 patients. Analysis of transmission rates revealed two vertical transmissions, likely intrauterine, and two vertical transmissions during the breastfeeding period. One transmission occurred at six weeks of age, possibly also intrauterine, and another at 50 weeks. However, the overall number of vertical transmissions was low, indicating a promising outcome. In the DOLPHIN2 study, which focused on late presenters starting treatment in the third trimester, participants were randomized to receive either dolutegravir or efavirenz. Among the 268 patients involved, there were three intrauterine transmissions and one transmission attributed to breastfeeding at 72 weeks in the efavirenz group. This translated to a low transmission rate of one out of 268 patients during breastfeeding. These findings suggest that dolutegravir-based regimens may be effective in reducing vertical transmission of HIV during both pregnancy and breastfeeding, offering hope for improved prevention strategies in this vulnerable population. 

The PROMISE-EPI study focused on postpartum interventions for HIV-positive mothers and their infants. After six to eight weeks postpartum, mothers who received antiretroviral treatment during pregnancy underwent viral load testing and were randomly assigned to intervention or control arms. In the control group, infants received standard postnatal prophylaxis, while in the intervention group, infants received lamivudine prophylaxis if the mother's viral load exceeded 1000 copies/mL. Results showed only one transmission in the intervention group compared to six in the control group. These findings highlight the effectiveness of early intervention in reducing vertical HIV transmission. Moreover, recent developments in high-income settings have led to the adoption of breastfeeding protocols for HIV-positive mothers, reflecting advancements in treatment and prevention strategies.

In recent years, there's been a shift in high-income settings towards allowing breastfeeding for HIV-positive mothers, with initiatives starting as early as 2018-2019. However, comprehensive studies are lacking, and available data mostly comprises case reports. For instance, in the UK, out of 203 cases and approximately 300 reported cases globally, there have been zero transmissions. Efforts like the WAVE group aim to establish a registry in Europe to gather more data for better decision-making. Despite sustained maternal viral suppression, rare cases of breast milk transmission have occurred. Possible factors include intermittent maternal adherence leading to undetected viral rebounds, subclinical mastitis, discordant plasma and breast milk viral load, cell-associated transmission, and altered infant gut integrity. Additionally, the use of antiretroviral therapy during pregnancy and breastfeeding might suppress infant viremia post-in utero transmission, potentially delaying the detection of transmission. 

When weighing the risks of breastfeeding, it's crucial to acknowledge the risks of not breastfeeding. While there is a risk of HIV transmission through breastfeeding, it's relatively low. Additionally, there's exposure to antiretroviral drugs, which is pertinent in pharmacology research. However, when comparing these risks to the potential risks of not breastfeeding, it's essential to recognize that formula feeding doesn't provide the same benefits as breast milk. Breastfeeding offers numerous advantages for both the mother and the child. Therefore, understanding the transfer of antiretrovirals into breast milk becomes significant. 

To study the transfer of antiretrovirals into breast milk, various methods can be employed. One approach is through spot sampling, where a woman using antiretrovirals and breastfeeding provides blood and milk samples at specific intervals during the breastfeeding period. These samples allow for the calculation of the milk-to-plasma ratio, providing insights into infant exposure. Another method is intensive sampling, which involves asking the mother to spend a day at the clinic for comprehensive blood and milk sample collection. This allows for the generation of full pharmacokinetic curves for both blood and milk, facilitating a detailed comparison. However, this approach highlights a limitation of spot sampling, as milk-to-plasma ratios may vary over time, with concentrations differing at different points in the pharmacokinetic curve. 

In-silico modeling offers a solution to the variability in milk-to-plasma ratios over time. These computer models simulate maternal physiology and drug properties to predict drug concentrations in both milk and plasma after dosing. By refining predictions with therapeutic drug monitoring (TDM) samples, the relative infant dose can be calculated, ensuring safe breastfeeding practices. Currently, there's a significant delay between FDA drug approval and knowledge of drug concentrations in breast milk, highlighting the need for expedited research. Recent studies, like one led by Caroline A. B. Popp, reveal varying drug concentrations in breast milk. While most antiretrovirals result in a safe relative infant dose (<10%), concerns remain about drug resistance if HIV transmission occurs due to low plasma concentrations. Thus, while low concentrations in breast milk may reduce toxicity risk, they raise concerns about HIV transmission and drug resistance in infants. 

The DHHS, a major American guideline, updated in January 2023, now supports breastfeeding for individuals with HIV who are on antiretroviral therapy (ART) and maintain a sustained undetectable viral load. They emphasize the importance of supporting women's choices regarding breastfeeding or formula feeding and encourage discussions about potential barriers to formula feeding. Efforts should be made to address these barriers to support the chosen feeding method effectively.

The EACS guidelines take a somewhat more cautious approach, stating that breastfeeding is not routinely recommended. However, in cases of persistent undetectable viral load, it may be considered, albeit as an exception rather than a standard practice. The decision to breastfeed should involve joint decision-making and consideration of general principles of postnatal prophylaxis and infant feeding. 

The EACS guidelines vary by country regarding infant pre-exposure prophylaxis during supported breastfeeding. Some countries offer it for the duration of breastfeeding, while others only recommend the usual post-birth regimen. For infants considered very low risk, single-agent postnatal prophylaxis is typically used for two to six weeks, although in some countries like Switzerland, neonates meeting very low-risk criteria may not require postnatal prophylaxis, even if breastfeeding. 

Surveys conducted in the Netherlands reveal that 76% of women living with HIV wish to breastfeed. Their motivations include the health benefits of breast milk for their infants, the emotional bonding associated with breastfeeding, concerns about HIV disclosure if they do not breastfeed, and financial considerations, as formula feeding can be costly. These findings underscore the importance of understanding the desires and concerns of women living with HIV when making decisions about infant feeding practices.

The key takeaways are- Breastfeeding with HIV presents complex considerations. While the U=U (undetectable equals untransmittable) principle applies, the actual risk remains uncertain, with transmission rates below 1% in women with suppressed viral loads. Breast milk offers unique benefits, contrasting with formula feeding. Most antiretrovirals are deemed safe for breastfeeding, but vigilance for resistance is crucial in case of transmission. Current guidelines advocate for shared decision-making, but there's ambiguity regarding postnatal prophylaxis during breastfeeding. At-risk women require extra HIV tests and may benefit from PrEP during pregnancy and breastfeeding. Overall, informed decision-making, support, and honest information are essential for women with HIV considering breastfeeding. 

European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2024, 27th April–30th April 2024, Barcelona, Spain